Since the beginning of the pandemic, there has been a surge of interest to learn more about SARS-CoV-2 and its many drug-targetable proteins. The main protease (Mpro) is an excellent candidate for a drug target because of its vital role in coronavirus replication and because there exists no human homologue, minimizing off-target effects. We find that Mpro is active at very high concentrations of dimethyl sulfoxide (DMSO), a common co-solvent for inhibitor candidates. The enzyme has enhanced activity with DMSO, reaching a maximum at 33%: the effect is also observed with other solvent mixtures at a similar dielectric i.e., polyethene glycol. Molecular dynamics simulations suggest DMSO does not bind to a specific site, but rather does a global conformational change of the enzyme, particularly near the active site and at the C-terminus. This work attempts to better understand Mpro dimerization, substrate binding, and interaction with its chemical environment and ultimately provide important details for robust design of inhibitors against Mpro and future variants of its kind.